1. Field of the Invention
The invention is related to general anesthetics and, more particularly, to aerosol formulations of general anesthetic agents that are liquid or solid at room temperature and are ordinarily administered intravenously, and the aerosolized delivery of these agents to the nasal, oral, and/or lung mucosa via patient inhalation.
2. Description of the Prior Art
A local anesthetic agent is a compound that reversibly depresses neuronal function, which results in a loss of the patient's ability to perceive pain and/or other sensations. A general anesthetic is one which causes a patient to lose consciousness. This type of agent is often referred to as a "hypnotic" agent. Nitrous oxide, which is often referred to as "laughing gas", is an example of an inhaled general anesthetic which is in common use. Halothane, isoflurane, and enflurane are examples of more potent, inhaled volatile general anesthetics that ante administered as a gas.
A number of hypnotic agents are also administered as an injected liquid solution or emulsion, as opposed to a gas. These agents are typically quick acting and may have desired analgesic properties, as well as advantageous systemic clearance properties upon termination of administration. These agents are ordinarily a liquid or solid at room temperature and have not, prior to this invention, been administered by aerosol.
Propofol, 2,6-diisopropylphenol (C.sub.12 H.sub.18 O), is one example of a rapidly acting hypnotic agent that is used as an intravenous general anaesthetic. It produces rapid and smooth induction of anaesthesia in one arm-brain circulation time, with good cardiovascular stability and a rapid and good quality of recovery with freedom from nausea.
Propofol in its pure form is a colorless liquid at room temperature (melting point 19.degree. C.). It is practically insoluble in water, thus it is difficult to formulate into a water soluble preparation suitable for intravenous administration. It was first used as a 1% active solution in 16% cremaphor EL as a solubilizing agent. When it became evident that cremaphor EL was associated with a significant risk of hypersensitivity reactions it was withdrawn from the market. Later it was reformulated in a soya bean oil emulsion: 1% weight in volume (w/v) aqueous emulsion in 10% w/v soya bean oil, 1.2% egg phosphatide, and 2.5% glycerol (see, Kanto, J. Clin. Pharm., Ther. Tox., Vol. 26, No. 1, 1988, pp.41-57). This reformulation overcame the solubility problem and provided a safer solubilizing technique than was achieved with cremaphor EL. The principle disadvantages of the reformulated product are a slight pain to the patient upon injection, and a short shelf-life, especially after opening the vial, owing to its susceptibility to contamination.
Propofol has many advantageous kinetic properties explaining its usefulness when administered by bolus dose intravenously for induction of anesthesia (1-2.5 mg/kg), including very rapid distribution, rapid elimination and high systemic clearance. A continuous infusion (75-300 .mu.g/kg/min) will maintain anesthesia as part of a balanced or a total intravenous anaesthetic; characterized by a rapid recovery on cessation of the infusion. These desirable kinetic properties are attributed to the high lipid solubility of this drug and its rapid metabolism. Infusions of sub-anesthetic doses (25-100 .mu.g/kg/min) of propofol can be used to provide sedation for patients undergoing procedures under local anesthesia or patients in intensive care on ventilatory support. The infusion allows rapid and easy control of the level of sedation and blood pressure. The rapid recovery of consciousness after the cessation of the infusion is an advantageous property of propofol.
Anesthetic and sedative techniques used in the ambulatory setting preferably have a low incidence of postoperative side effects, thus ensuring an optimum patient safety by allowing a rapid return to pre-operative status. Propofol's predictable recovery and favorable side effect profile; even after repeated bolus doses or a titrated continuous infusion, make it well suited for induction and maintenance of anesthesia or sedation during short ambulatory procedures.
In the pediatric patient population, intravenous induction of anesthesia remains a problem because of the difficulty in obtaining vascular access in the awake and frightened child. Inhalational anaesthesia using potent volatile anesthetic agents such as halothane are routinely used for induction of anesthesia in many situations in order to avoid the need for intravenous access before the child is asleep. Alternatively, a sedative agent can be administered. Sedation needs to administered ahead of time as onset of action is slow. The use of sedative agents requires the child to be observed until the anesthetic is given and it prolongs the recovery time after a short procedure. Intranasal midazalam using the water-soluble intravenous preparation has recently been advocated. It has the disadvantages of stinging on administration, slow onset time and a slow recovery.